Acute Lung Injury (ALI) is a common complication of sepsis and trauma and is associated with mortality rates of over 20%. Candidate gene studies suggest a role for common genetic variation in determining host susceptibility to ALI in critically ill patients. However, variants studied to date account for only a small proportion of the variability in risk of an individual to develop ALI after exposure to apparently similar risk factors such as sepsis or traumatic injury. We hypothesize that additional common genetic variants associated with increased risk for ALI can be discovered in a large group of patients at-risk for ALI using a genome- wide association study (GWAS). We propose to capitalize on existing genomic DNA samples and associated rich phenotypic data collected as part of the ARDSnet consortium clinical trials in this genome-wide search for ALI risk alleles. We will leverage well-phenotyped samples collected as part of studies performed by members of the iSPAAR (identification of SNPs Predisposing to Altered ALI Risk) consortium to provide an unprecedented sample size for a genetic study in the critically ill. Through the following specific aims we will provide new insight on ALI pathogenesis and identify novel markers of risk for ALI that can be tested in future studies for utility in risk stratification and identification of subjects at high-risk for poor outcomes that might benefit most from new therapeutic interventions. We will also generate an invaluable new resource for the study of genetics underlying risk for ALI that will facilitate many future studies that were previously unfeasible given the lack of adequate samples sizes and dense genotypic information. Taken together, these contributions will represent a rapid major advancement in the field of ALI pathogenesis and prediction. PUBLIC HEALTH RELEVANCE: The proposed studies are highly relevant to human health. We will investigate the genetic factors that modify an individual's susceptibility to acute lung injury (ALI), which affects more than 200,000 patients per year in the U.S. and is associated with mortality of 20-25%. Our studies will identify new genes that contribute to the onset or severity of ALI, and these genes could become new targets for treatment and risk stratification. We are using the power of genetic investigation to move towards a personalized approach to the care of critically ill patients.